US6509358B2ExpiredUtilityPatentIndex 57
Piperidino-phenyl amino squarate and thiadiazole dioxide beta-3 adrenergic receptor agonists
Est. expiryJul 17, 2020(expired)· nominal 20-yr term from priority
C07D 211/58C07D 417/12
57
PatentIndex Score
2
Cited by
35
References
12
Claims
Abstract
This invention provides compounds of Formula I having the structureand X are as defined hereinbefore, or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenic inflammation, glaucoma, ocular hypertension and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the goup consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 , wherein
(a) phenyl optionally substituted with 1-3 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 —;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
R 2 and R 3 are each, independently, hydrogen or alkyl of 1-10 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2
n=1-2
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , which is
a) 4-((2S)-2-hydroxy-3-{1-[4-(4-octylamino-1,1-dioxo-1H-1.lambda(6).-[1,2,5]thiadiazol-3-ylamino)-phenyl]-piperidin -4-ylamino}-propoxy)-phenol;
b) 4-{(2S)-3-[1-(4-{4-[2-(4-fluoro-phenyl)-ethylamino]-1,1-dioxo-1H-1.lambda(6).-[1,2,5]thiadiazol-3-ylamino}-phenyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenol;
c) (S)-4-{2-hydroxy-3-[1-(4-{4-[2-(4-methoxy-phenyl)-ethylamino]-1,1-dioxo-1H-1.lambda(6).-[1,2,5]thiadiazol-3-ylamino}-phenyl)-piperidin-4-ylamino]-propoxy}-phenol;
d) methyl (2R)-2-{[2-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}anilino)-3,4-dioxocyclobut-1-en-1-yl]amino}-3-phenylpropanoate;
e) methyl 2-{[4-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}anilino)-1,1-dioxido-1,2,5-thiadiazol -3-yl]amino}-3-phenylpropanoate;
f) methyl {[4-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}anilino)-1,1-dioxido-1,2,5-thiadiazol -3-yl]amino}acetate;
or a pharmaceutically acceptable salt thereof.
6. A method of treating metabolic disorders resulting directly or indirectly from insulin resistance or hyperglycemia in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
7. A method of treating or inhibiting type II diabetes in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of Formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
8. A method of lowering serum glucose levels in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
9. A method of treating or inhibiting urinary incontinence in a mammal in need thereof which comprises providing to said mammal an effective amount of a compound of formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
10. A method of treating or inhibiting atherosclerosis, gastrointestinal disorders, neurogenic inflammation, glaucoma, or ocular hypertension in a mammal in need thereof, which comprises providing to said mammal a β 3 -AR agonistic effective amount of a compound of formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof.
11. A method of increasing the lean meat to fat ratio in a mammal in need thereof, which comprises providing to said mammal a β 3 -AR effective amount of a compound of formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected-from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n 1-2
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition which comprises a therapautic effective amount of a compound of formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
Y is hydroxy, halogen, cyano, —SO m R 2 , —SO n NR 2 R 3 , —NHSO 2 R 2 , —NR 2 R 3 , alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR 2 , or —CO 2 R 2 ;
X is —OCH 2 — or a bond;
R 1 is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the group consisting of halogen; hydroxy; phenyl optionally mono- or di-substituted with Z; oxo; —CO 2 H; —CO 2 R 2 ; amino; —NR 2 R 3 ; and —NHCOR 2 ;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms; or
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R 2 and R 3 are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is hydroxy, halogen, alkyl of 1-10 carbon atoms, —CO 2 R 2 , benzyloxy, —NHC(O)NHR 2 , —NR 2 R 3 , —OR 2 , —COR 2 , —S(O) m R 2 ; or —S(O) n NR 2 R 3 ;
m=0-2;
n=1-2
or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.Cited by (0)
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